Excitability decreasing central motor plasticity is retained in multiple sclerosis patients

ABSTRACT: BACKGROUND: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. METHODS: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. RESULTS: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 +/- 22 % of baseline amplitude, p < 0.001) and in MS patients (69 +/- 18 %, p < 0.001). In contrast, post-cTBS force production performance was only impaired in controls (2.2 +/- 2.8, p = 0.011), but not in MS patients (2.0 +/- 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. CONCLUSIONS: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS.     

F responses and central motor conduction in multiple sclerosis

Two electrophysiological investigations were used to study 18 patients with multiple sclerosis — F wave characteristics including amplitude, persistence and frequency, which can provide a measure of motoneurone excitability, and magnetic stimulation of the cortex, which enables measurement of conduction along central motor pathways. There was an increase in the mean amplitude and persistence of the F response in patients with abnormal central motor conduction (CMC), although no correlation between the degree of abnormality of CMC and increase in F response amplitude was found. Increase in mean amplitude and persistence of the F response were also found in patients with normal CMC but clinical evidence of a UMN disorder (spasticity and/or weakness); there was no correlation, however, between any single F response characteristic and any particular clinical sign. CMC appears to be the preferred test for detecting subclinical motor lesions in MS: of the patient sides with normal clinical examination, 36% showed abnormal CMC, whereas 23% showed abnormal F responses.     

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction, including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favoured over long-term depression in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted towards preventing synaptic pathology can be developed.     

Orienting reaction in patients with multiple sclerosis

A polygraphic study of the somatic (EMG), autonomic (finger plethysmogram, galvanic skin reaction, respiration, pulse, and EEG (acoustic-evoked potential and EEG-blocking reaction) components of the orienting reaction elicited by an auditory stimulus was performed in 71 patients with multiple sclerosis and in 74 matched normal subjects (control group). The study showed a significantly less intense orienting reaction in patients with multiple sclerosis than in control normal subjects. The severity of this responsiveness disturbance depended on the patients' age at symptom onset, major symptom types on admission, and the relapse frequency. The orienting reaction changes found in patients with multiple sclerosis may be ascribed to the diffuse demyelinating lesions in the nervous system of these patients, which generate, apart from the so polymorphous clinical manifestations of this disease, also important responsiveness disturbances.     

Oxidative stress in patients with multiple sclerosis

It is well known that brain and nervous system cells are prone to oxidative damage because of their relatively low content of antioxidants, especially enzymatic ones, and of the high levels of both membrane polyunsaturated fatty acids (PUFA) and iron easily released from injured cells. We have investigated the oxidative stress in the blood (plasma, erythrocytes and lymphocytes) of 28 patients affected with multiple sclerosis (MS) and of 30 healthy age matched controls, by performing a multiparameter analysis of non-enzymatic and enzymatic antioxidants--Vitamin E (Vit. E), ubiquinone (UBI), reduced and oxidized glutathione (GSH, GS-SG), superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) and fatty acid patterns of phospholipids (PL-FA). PL-FA and Vit. E were assayed by GC-MS; UBI and GSH/GS-SG by HPLC; SOD, GPX and CAT by spectrophotometry. In comparison to controls, patients with MS showed significantly reduced levels of plasma UBI (0.21 +/- 0.10 vs. 0.78 +/- 0.08 mg/ml, p < 0.001), plasma Vit. E (7.4 +/- 2.1 vs. 11.4 +/- 1.8 mg/ml, p < 0.01), lymphocyte UBI (8.1 +/- 4.0 vs. 30.3 +/- 7.2 ng/ml blood, p < 0.001) and erythrocyte GPX (22.6 +/- 5.7 vs. 36.3 +/- 6.4 U/g Hb, p < 0.001). This blood antioxidant deficiency was associated with plasma levels of PL-PUFA--especially C20:3 n-6 and C20:4 n-6--significantly higher than controls. In conclusion, the blood of patients with MS shows the signs of a significant oxidative stress. The possibility of counteracting it by antioxidant administration plus an appropriate diet, might represent a promising way of inhibiting the progression of the disease. Antioxidant supplements should include not only GSH repleting agents, but also Vit. E, ubiquinol, and selenium.     

Excitability changes in the crustacean motor axon following activity

It has been shown experimentally that the crustacean motor axon is supernormally excitable following a train of action potentials (Zucker 1974). Such a phenomenon can lead to recruitment of terminals which are unexcited at low rates of stimulation. Although currents underlying the crustacean motor axon have been characterized (Connor et al. 1977), it is not known whether this membrane model accounts for a supernormal period, what might cause superexcitablity in this model, or how excitability might change during repetitive stimulation. In present study, it is demonstrated that the crustacean motor axon model does predict a supernormal period, that the supernormal period results from slow recovery from inactivation of the transient potassium, or A, current, and that supernormal excitability is enhanced by repetitive stimulation.     

Erythrocyte membrane glycerophospholipid organization is normal in multiple sclerosis

The phospholipid composition of erythrocyte membranes from patients with multiple sclerosis (MS) was found to be normal, in agreement with previous reports. The transbilayer asymmetry of the glycerophospholipids in MS red cells was probed using bee venom phospholipase A₂ and was also found not to be significantly different from normal. Abnormal membrane glycerophospholipid organisation is therefore not involved in the increased red cell size, osmotic fragility, and electrophoretic mobility associated with MS.     

Driving plasticity in human adult motor cortex is associated with improved motor function after brain injury

Changes in somatosensory input can remodel human cortical motor organization, yet the input characteristics that promote reorganization and their functional significance have not been explored. Here we show with transcranial magnetic stimulation that sensory-driven reorganization of human motor cortex is highly dependent upon the frequency, intensity, and duration of stimulus applied. Those patterns of input associated with enhanced excitability (5 Hz, 75% maximal tolerated intensity for 10 min) induce stronger cortical activation to fMRI. When applied to acutely dysphagic stroke patients, swallowing corticobulbar excitability is increased mainly in the undamaged hemisphere, being strongly correlated with an improvement in swallowing function. Thus, input to the human adult brain can be programmed to promote beneficial changes in neuroplasticity and function after cerebral injury.     

Inapparent visual field defects in multiple sclerosis patients

To assess inapparent visual field defects in patients with multiple sclerosis free from optic neuritis. During 5 years period 120 patients with multiple sclerosis were examined at the University Department of Ophthalmology, Zagreb University Hospital Center. They were divided into three groups with 40 patients each: patients with acute unilateral optic neuritis, referred to ophthalmologist and treated with pulsed steroid therapy; patients with subjective feeling of blurred vision, normal visual acuity and no signs of acute optic neuritis; and patients free from subjective signs of visual impairment. Study patients underwent standard ophthalmologic examination and visual field testing in photopia by use of quantitative kinetic Goldmann perimetry. The initial and control examination by visual field testing were performed at least 6 months apart. Study results showed 65% of multiple sclerosis patients to have visual field defects without subjective signs of impaired vision. The most common defects were mild to moderate visual field narrowing with blind spot enlargement and depression from above. The following results were recorded: acute optic neuritis group: normal in 13/40 (32.5%) for the affected eyes and 27/40 (67.5%) for fellow eyes; mild visual field narrowing in 4/40 (10%) for the affected eyes and 10/40 (25%) for fellow eyes; moderate visual field narrowing with blind spot enlargement in 14/40 (35%) for the affected eyes and 1/40 (2.5%) for fellow eyes; and paracentral and arcuate scotomata in 9/40 (22.5%) for the affected eyes and 2/40 (5%) for fellow eyes; subjective symptom group: normal in 8/40 (20%) for the affected eyes and 11/40 (27.5%) for fellow eyes; mild visual field narrowing in 11/40 (27.5%) for the affected eyes and 16/40 (40%) for fellow eyes; moderate visual field narrowing with blind spot enlargement in 18/40 (45%) for the affected eyes and 10/40 (25%); andparacentral and arcuate scotomata in 3/40 (7.5%) for both affected and fellow eyes; and subjective symptom-free group: normal in 24/80 (30%), mild visual field narrowing in 22/80 (27.5%) moderate visual field narrowing with blind spot enlargement in 24/80 (30%); and paracentral and arcuate scotomata in 10/80 (12.5%). The presence of subclinical form of optic nerve involvement could be demonstrated in a very early stage of multiple sclerosis by the introduction of visual field testing in the standard examination protocol.     

Genomic effects of IFN-beta in multiple sclerosis patients

The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-beta-1a treatment regimen in multiple sclerosis patients and to examine the molecular mechanisms potentially capable of causing heterogeneity in response to therapy. In this open-label pharmacodynamic study design, peripheral blood was obtained from eight relapsing-remitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 micro g of IFN-beta-1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for >4000 known genes. IFN-beta-1a treatment resulted in selective, time-dependent effects on multiple genes. The mRNAs for genes implicated in the anti-viral response, e.g., double-stranded RNA-dependent protein kinase, myxovirus resistance proteins 1 and 2, and guanylate binding proteins 1 and 2 were rapidly induced within 1-4 h of IFN-beta treatment. The mRNAs for several genes involved in IFN-beta signaling, such as IFN-alpha/beta receptor-2 and Stat1, were also increased. The mRNAs for lymphocyte activation markers, such as IFN-induced transmembrane protein 1 (9-27), IFN-induced transmembrane protein 2 (1-8D), beta(2)-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFN-beta treatment induces specific and time-dependent changes in multiple mRNAs in lymphocytes of multiple sclerosis patients that could provide a framework for rapid monitoring of the response to therapy.     

Calcium concentration in brains from multiple sclerosis patients

Calcium (Ca) concentrations were studied in the central nervous system (CNS) of four patients with definite multiple sclerosis (MS, average age 49 yr) and five controls (average age 68 yr). The Ca concentration was determined by neutron activation analysis in autopsy samples taken from the 26 subanatomical regions of CNS tissues. Although the mean Ca concentration in the 26 CNS regions combined was higher in the four MS patients than in the controls, the content of white matter was lower. Whether or not this significantly lower Ca concentration found in the white matter of MS patients plays an important role in the demyelinating process remains unclear, although that lower concentration seems not be age dependent, but MS specific.     

Excitability of the soma in central nervous system neurons

The ability of the soma of a spinal dorsal horn neuron, a spinal ventral horn neuron (presumably a motoneuron), and a hippocampal pyramidal neuron to generate action potentials was studied using patch-clamp recordings from rat spinal cord slices, the "entire soma isolation" method, and computer simulations. By comparing original recordings from an isolated soma of a dorsal horn neuron with simulated responses, it was shown that computer models can be adequate for the study of somatic excitability. The modeled somata of both spinal neurons were unable to generate action potentials, showing only passive and local responses to current injections. A four- to eightfold increase in the original density of Na(+) channels was necessary to make the modeled somata of both spinal neurons excitable. In contrast to spinal neurons, the modeled soma of the hippocampal pyramidal neuron generated spikes with an overshoot of +9 mV. It is concluded that the somata of spinal neurons cannot generate action potentials and seem to resist their propagation from the axon to dendrites. In contrast, the soma of the hippocampal pyramidal neuron is able to generate spikes. It cannot initiate action potentials in the intact neurons, but it can support their back-propagation from the axon initial segment to dendrites.     

Progression in multiple sclerosis is associated with low endogenous NCAM

Multiple sclerosis (MS) is a CNS disorder characterized by demyelination and neurodegeneration. Although hallmarks of recovery (remyelination and repair) have been documented in early MS, the regenerative capacity of the adult CNS per se remains uncertain with the wide held belief that it is either limited or non‐existent. The neural cell adhesion molecule (NCAM) is a cell adhesion molecule that has been widely implicated in axonal outgrowth, guidance and fasciculation. Here, we used in vitro and in vivo of MS to investigate the role of NCAM in disease progression. We show that in health NCAM levels decrease over time, but this occurs acutely after demyelination and remains reduced in chronic disease. Our findings suggest that depletion of NCAM is one of the factors associated with or possibly responsible for disease progression in MS.     

Somatosensory impairments in patients with multiple sclerosis: association with dynamic postural control and upper extremity motor function

Abstract

Purpose: We planned this study to bring attention to the somatosensory impairments in patients with multiple sclerosis (PwMS) and to investigate relationship of somatosensory impairments with dynamic postural stability and upper extremity motor function.

Methods: Seven males and 23 females, 30 patients with mean EDSS 2.9 (SD = 1.4), aged between 18 and 65 years (mean = 41.43?±?14.90 years) were included in this clinical study. Light touch sensorial assessment was made with Semmes Weinstein monofilament test and proprioception by distal proprioception test. Hand strength was measured by the Jamar dynamometer, fine motor skill was examined with nine-hole peg test, functional reach test in sitting and standing position was applied. Nottingham Extended Activities of Daily Living Scale (NEADLS) was used to measure everyday activities.

Results: We found a negative and moderate correlation between FRT in standing and light touch of the middle of the heel (right: –0.515), metatarsal bone (right r: 0.453, left r: –0.426), and medial of the foot (right r: –0.462). There was a negative and moderate correlation between NEADLS and light touch of the metatarsal bone (right r: –0.564, left r: –0.472), medial of the foot (right r: –0.531, left r: –0.479), and lateral of the foot (right r: –0.526). We found a positive and moderate correlation between proprioception of the ankle (right r: 0.421 left r: 0.588) and NEADLS.

Conclusions: We found impairment in light touch and proprioception and, associations between sensorial functions and dynamic postural stability in PwMS. Also impaired sensorial functions cause dependent patients in daily living activities. In the assessment of balance and falling risk, independency in daily living activities; foot light touch and proprioception sense should be taken into account, hence it may provide guidance in planning rehabilitation programmes.

Abbreviations: MS: multiple sclerosis; PwMS: patients with multiple sclerosis; VAS: visual analogue scale; FRT: functional reach test; 9-HPT: Nine-hole peg test; EDSS: The Expanded Disability Status Scale; NEADLS: Nottingham Extended Activities of Daily Living Scale